Animal research in progress at Bath
We have used zebrafish and mice in our research to better understand a human disease gene and early embryonic development.
Understanding a human disease gene using zebrafish genetic models
In humans, diseases affecting pigment cells are rather common, for example: albinism, melanoma and vitiligo. One such important class of diseases are the Waardenburg syndromes in which patients have large areas of skin devoid of pigment cells, while the rest of the skin is normal.
One gene associated with Waardenburg syndrome is called SOX10, and it can readily be recognised as encoding a protein that drives the expression of many target genes. The question that remained unanswered, however, was what is the main purpose of those target genes i.e. what biological process does SOX10 perform?
We identified the first zebrafish models for the type of Waardenburg syndrome associated with SOX10, and showed that they were in fact caused by mutations in the zebrafish sox10 gene. In subsequent work we have identified the common theme in the role of Sox10 in pigment cells, but also in other cell types that share a common stem cell origin.
Our work, confirmed in mammalian models, shows that SOX10 seems to function primarily to direct stem cells to develop into specific individual cell types, including pigment cells and neurons.
We are now extending this work, in collaboration with a consortium of human and mouse geneticists, trying to understand why the human conditions associated with SOX10 mutations have very variable disease effects, sometimes mild, sometimes very severe.
We have developed a zebrafish embryo-based phenotypic rescue assay to assess the activities of the mutant forms of the human SOX10 protein, and are now attempting to engineer humanised’ zebrafish mutants to assess more precisely their effects in vivo.
Understanding early embryonic development using a mouse model and alternative methods
The key question in Developmental Biology is how cells make decisions in order to generate tissues and organs in a coordinated manner.
If there is any problem in this cell decision making, the embryo will not grow, resulting in miscarriage even before the woman acknowledges the pregnancy. It has been calculated that 76% of miscarriages happen during this stage of embryo development.
Every animal starts as a single cell (the fertilized oocyte) which starts dividing, to form different groups of cells: each of these groups will form all the tissues present in the adult but also those required to support embryonic growth.
In the first decision, some cells separate from the rest to form the placenta.
In the second decision, cells decide to become part of the embryo proper, while others form the precursors of the yolk sac. In our lab, we are studying this second decision which happens between 3.5 and 4.5 days after fertilization in the mouse (figure 1).
The mouse is an ideal model to understand this process as there are clear similarities with humans and important discoveries were made initially in this model system, before undertaking similar studies in humans.
However, in order to reduce the number of animals used for experimentation, we also use mouse embryonic stem cells (mESCs) which have been modified to allow the study of this decision (figure 2).
The use of mESCs to understand embryonic development is a new approach which is allowing rapid progress in the early embryo development field.